Early detection of PDAC is an area of highest priority and an unmet need for advancing public health in the United States. Certain sub-groups of patients, such as those with mucinous pancreatic cysts are at higher risk for progression to PDAC, but even in these cohorts, there is potential for over-diagnosis, underscoring the need for biomarkers that can accurately distinguish aggressive versus indolent cysts. The long term goal of our EDRN Clinical Validation Center (CVC), comprised of MD Anderson (MDACC), University of Utah and Indiana University, is to implement a multi-institutional framework for collecting the highest quality biospecimens from patients with a variety of well-defined pancreatic pathologies in order to conduct biomarker validation studies for early detection of PDAC that conform to EDRN-defined Phase 2 and Phase 3 study design. Specifically, this CVC will prospectively recruit at least 600 patients with early stage (resected) PDAC, at least 300 patients with surgically resected pancreatic cystic lesions of varying histology and grades of dysplasia, at least 400 benign pancreatic diseases (including chronic pancreatitis, benign cysts, endocrine tumors of low malignant potential), at least 300 patients with non-resected pancreatic cystic lesions that have follow up of 2 years or greater without evidence for progression, and at least 300 control patients with non- pancreatic diseases, in order to obtain plasma and serum samples from these subjects for biomarker validation studies. Additionally, we will obtain cyst fluid samples from all patients with pancreatic cystic lesions, both surgically resected and those being followed by endoscopic imaging. In accordance with the EDRN principles, these biospecimens will be utilized in facilitating collaborations with other BDLs, for biomarker discovery and validation studies. Preliminary data generated in our CVC has identified a focused panel of overexpressed autoantibodies and antigens (ERBB2, TNC, ESR1, CACNA1D and CDKN2AIP) that significantly improves CA19-9 AUC in both diagnostic and pre-diagnostic cohorts. We will use a hybrid array platform developed at Fred Hutchinson Cancer Research Center (FHCRC) that is capable of quantifying both antigens and autoantibodies from plasma, and use this platform to complete three PRoBE compliant biomarker studies: Study 1 will be an EDRN-defined Phase 3 study in pre-diagnostic PDAC samples (n=158) and matched controls (n=158) from WHI and PLCO cohorts, followed by an EDRN-defined Phase 2 case control study of early stage (resectable) PDAC (N = 300) versus chronic pancreatitis (N = 300) and non-pancreatic disease controls (N=300); Study 2 will be an EDRN-defined Phase 3 study in PLCO pre-diagnostic PDAC samples (n=160), and matched controls (n=160); and Study 3 will be an EDRN-defined Phase 2 case control study of pancreatic cystic neoplasms with high-grade dysplasia or cancer (N =150) versus pancreatic cystic neoplasms with surgically confirmed low-grade dysplasia and non-mucinous cystic lesions (N=150), as well as low-risk cyst with adequate follow up that are followed without surgery (N=150).